Historical Overview

The therapy for GI diseases changed markedly with the introduction of histamine (H2) receptor antagonists in the 1970s, which reduced surgical intervention and ameliorated problems with patient compliance.

With Schwarz's statement of 'no acid - no ulcer' in 1910, the treatment of reflux esophagitis and gastroduodenal ulcers required new approaches to provide effective control of gastric acid secretion (see 6.27 Gastric and Mucosal Ulceration). In the late 1960s, antiacids were available, but these only partially neutralized the gastric acid that had been secreted, and therefore symptom control and ulcer healing rates were unsatisfactory. The persistence and the intuition of Black and Duncan led to the discovery of H2 receptor antagonists.2

The first H2 receptor antagonist developed was burimamide, followed by metiamide. With minimal structural alterations, Brimblecombe etal.3 developed cimetidine, the first $1 billion a year blockbuster drug (see 8.03 Medicinal Chemistry as a Scientific Discipline in Industry and Academia: Personal Reflections). The modification of the chemical structure of cimetidine, with elimination of the imidazole ring, led to ranitidine, the pharmacokinetic characteristics of which provided improved patient compliance. These drugs provided effective inhibition of production and release of gastric acid via a pharmacologically proven mechanism, and became the gold standard therapy for peptic ulcers during the 1980s, leading to a marked improvement in the quality of life for a large number of patients, and substantial reductions in the societal costs of the treatment and incapacitation associated with gastric ulceration.

However, H2 receptor antagonists do not block parietal cell stimulation by agonists other than histamine (e.g., vagal acetylcholine interacting with parietal cell muscarinic M3 receptors, or gastrin released from G cells), develop rapid tolerance during therapy due to the elevation of cAMP levels in parietal cells, and are more effective in inhibiting nocturnal than daytime acid secretion.4

These shortcomings were overcome with the discovery and development of proton pump inhibitors (PPIs) during the late 1980s. The stimulation of several receptors on parietal cells converge on the final pathway to increase acid secretion via the H + /K+-ATPase pump.5 By selectively blocking this pump, a novel class of efficient antisecretory agents was developed. Their superior antisecretory potency, long-lasting efficacy, and pharmacokinetic characteristics have established these compounds as drugs of choice for the therapy of peptic ulcers. Similarly to the H2 receptor antagonists, lansoprazole, pantoprazole, and rabeprazole were subsequently developed by modifying the chemical structure of omeprazole, the first PPI discovered (see 8.17 Omeprazole).5 In contrast to H2 receptor antagonists, all PPIs possess a common structural element, the benzidamizole ring. The last compound of this class to be launched on the market was esomeprazole, the active isomer of omeprazole, which in 2004 was fourth best selling drug worldwide.

Another important discovery that changed peptic ulcer therapy occurred also during the 1980s, with the first culture of Helicobacter pylori. In April 1982, Warren and Marshall at the Royal Perth Hospital in Australia, after a long period of negative attempts, succeeded isolating this bacterium, at that time called Campylobacterpyloridis.6 The close association of the bacterium with gastritis and peptic ulcer was subsequently confirmed by Marshall and co-workers in 114 infected patients.6'7 H. pylori, a Gram-negative spiral organism localized on the luminal surface of epithelial cells, is the main cause of chronic gastritis. H. pylori infection is usually acquired in childhood and early adulthood, and up to 50% of the world population is infected, many without symptoms. In countries with low standards of hygiene, the infection rate is high, due to fecal-oral and oral-oral transmission of the bacterium. The infection usually remains in the stomach for decades, finally leading to atrophy and intestinal metaplasia. In a few patients this metaplasia may lead to dysplasia and gastric carcinoma.

H. pylori infects only gastric-type mucosal tissue, but when such tissue occurs in the duodenum (gastric metaplasia), the bacterium can cause duodenitis, and, with the aid of acid and pepsin, induce duodenal ulcers. In this tissue, H. pylori duodenitis is necessary but not sufficient for ulcer formation. Nonmalignant gastric ulcers and B cell gastric lymphoma are also associated with H. pylori infection. Gastric cancer is the second most common cause of cancer mortality worldwide, and a recent meta-analysis has shown that patients infected with H. pylori were nearly six times more likely to develop adenocarcinoma than uninfected controls,8 while eradication of H. pylori improved gastric atrophy and intestinal metaplasia, thought to be premalignant changes.9

Owing to the availability of inexpensive and noninvasive tests such as the urea breath and the stool antigen tests, it is nowadays very easy to diagnose the presence of H. pylori in the stomach, and then to eradicate it by the use of at least two antibiotics (amoxicillin, clarithromycin and/or metronidazole) along with an antisecretory agent such as a PPI or an H2 receptor antagonist.

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